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DK2482806T3 - Pharmaceutical composition, pharmaceutical dosage form, method of preparation thereof, methods of treatment and uses thereof - Google Patents

Pharmaceutical composition, pharmaceutical dosage form, method of preparation thereof, methods of treatment and uses thereof Download PDF

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Publication number
DK2482806T3
DK2482806T3 DK10759923.5T DK10759923T DK2482806T3 DK 2482806 T3 DK2482806 T3 DK 2482806T3 DK 10759923 T DK10759923 T DK 10759923T DK 2482806 T3 DK2482806 T3 DK 2482806T3
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pharmaceutical composition
inhibitor
sglt
metformin
tablet
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DK10759923.5T
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Danish (da)
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Peter Schneider
Wolfram Eisenreich
Nantharat Pearnchob
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Boehringer Ingelheim Int
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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    • A61P3/04—Anorexiants; Antiobesity agents
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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Description

DESCRIPTION
Technical Field of the Invention [0001] The present invention relates to solid pharmaceutical compositions comprising fixed dose combinations of the SGLT-2 inhibitor drug 1-chloro-4-(3-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and the partner drug metformin hydrochloride, and their use to treat certain diseases.
[0002] In a more detailed aspect, the present invention relates to oral solid dosage forms for fixed dose combination (FDC) of 1-chloro-4-(P-D-glucopyranos-1 -yl)-2-[4-(('Sj-tetrahydrofuran-3-ylo>y)-benzyl]-benzene and metformin hydrochloride.
[0003] In addition the invention relates to the pharmaceutical composition and of the pharmaceutical dosage form for use in the treatment and/or prevention of selected diseases and medical conditions, in particular of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose and hyperglycemia inter alia.
Background of the Invention [0004] Type 2 diabetes is an increasingly prevalent disease that due to a high frequency of complications leads to a significant reduction of life expectancy. Because of diabetes-associated microvascular complications, type 2 diabetes is currently the most frequent cause of adult-onset loss of vision, renal failure, and amputations in the industrialized world. In addition, the presence of type 2 diabetes is associated with a two to five fold increase in cardiovascular disease risk.
[0005] After long duration of disease, most patients with type 2 diabetes will eventually fail on oral therapy and become insulin dependent with the necessity for daily injections and multiple daily glucose measurements.
[0006] The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated that intensive treatment with metformin, sulfonylureas or insulin resulted in only a limited improvement of glycemic control (difference in HbA1c -0.9%). In addition, even in patients within the intensive treatment arm glycemic control deteriorated significantly over time and this was attributed to deterioration of β-cell function. Importantly, intensive treatment was not associated with a significant reduction in macrovascular complications, i.e. cardiovascular events. Therefore many patients with type 2 diabetes remain inadequately treated, partly because of limitations in long term efficacy, tolerability and dosing inconvenience of existing antihyperglycemic therapies.
[0007] Oral antidiabetic drugs conventionally used in therapy (such as e.g. first- or second-line, and/or mono- or (initial or addon) combination therapy) include, without being restricted thereto, metformin, sulphonylureas, thiazolidinediones, glinides and a-glucosidase inhibitors.
[0008] The high incidence of therapeutic failure is a major contributor to the high rate of long-term hyperglycemia-associated complications or chronic damages (including micro- and macrovascular complications such as e.g. diabetic nephrophathy, retinopathy or neuropathy, or cardiovascular complications) in patients with type 2 diabetes.
[0009] Therefore, there is an unmet medical need for methods, medicaments and pharmaceutical compositions with a good efficacy with regard to glycemic control, with regard to disease-modifying properties and with regard to reduction of cardiovascular morbidity and mortality while at the same time showing an improved safety profile.
[0010] SGLT2 inhibitors represent a novel class of agents that are being developed for the treatment or improvement in glycemic control in patients with type 2 diabetes. Glucopyranosyl-substituted benzene derivative are described in the prior art as SGLT2 inhibitors, for example in WO 01/27128, WO 03/099836, WO 2005/092877, WO 2006/034489, WO 2006/064033, WO 2006/117359, WO 2006/117360, WO 2007/025943, WO 2007/028814, WO 2007/031548, WO 2007/093610, WO 2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940. The glucopyranosyl-substituted benzene derivatives are proposed as inducers of urinary sugar excretion and as medicaments in the treatment of diabetes.
[0011] Renal filtration and reuptake of glucose contributes, among other mechanisms, to the steady state plasma glucose concentration and can therefore serve as an antidiabetic target. Reuptake of filtered glucose across epithelial cells of the kidney proceeds via sodium-dependent glucose cotransporters (SGLTs) located in the brush-border membranes in the tubuli along the sodium gradient. There are at least 3 SGLT isoforms that differ in their expression pattern as well as in their physico-chemical properties. SGLT2 is exclusively expressed in the kidney, whereas SGLT 1 is expressed additionally in other tissues like intestine, colon, skeletal and cardiac muscle. SGLT3 has been found to be a glucose sensor in interstitial cells of the intestine without any transport function. Potentially, other related, but not yet characterized genes, may contribute further to renal glucose reuptake. Under normoglycemia, glucose is completely reabsorbed by SGLTs in the kidney, whereas the reuptake capacity of the kidney is saturated at glucose concentrations higher than 10mM, resulting in glucosuria ("diabetes mellitus"). This threshold concentration can be decreased by SGLT2-inhibition. It has been shown in experiments with the SGLT inhibitor phlorizin that SGLT-inhibition will partially inhibit the reuptake of glucose from the glomerular filtrate into the blood leading to a decrease in blood glucose concentrations and to glucosuria.
Aim of the present invention [0012] The aim of the present invention is to provide a pharmaceutical composition comprising the SGLT2 inhibitor 1-chloro-4-(3-D-glucopyranos-1-yl)-2-[4-(('SJ-tetrahydrofuran-3-yloxy)-benzyl]-benzene and the partner drug metformin hydrochloride which has high content uniformity for the SGLT2 inhibitor and the partner drug.
[0013] Another aim of the present invention is to provide a pharmaceutical composition comprising the SGLT2 inhibitor 1-chloro-4-(P-D-glucopyranos-1-yl)-2-[4-((S>tetrahydrofuran-3-yloxy)-benzyl]-benzBne and metformin hydrochloride which has very high drug load for the partner drug and very low drug load for the SGLT2 inhibitor.
[0014] Another aim of the invention is to provide a pharmaceutical composition comprising the SGLT2 inhibitor 1-chloro-4-(P-D-glucopyranos-1-yl)-2-[4-(('SJ-tetrahydrofuran-3-yloxy)-benzyl]-benzene and metformin hydrochloride which allows an effective production with regard to time and costs of pharmaceutical dosage forms.
[0015] Another aim of the present invention is to provide a pharmaceutical composition comprising the SGLT-2 inhibitor 1-chioro-4-(P-D-giucopyranos-1-yl)-2-[4-(('S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and metformin hydrochloride which avoids or reduces sticking and capping during the production process of the composition.
[0016] Another aim of the present invention is to provide a pharmaceutical composition comprising the SGLT-2 inhibitor 1-chloro-4-(p-D-glucopyranos-1-yl)-2-[4-(('SJ-tetrahydrofuran-3-yloxy)-benzyl]-benzene and metformin hydrochloride which avoids or reduces filming during the production process of the composition.
[0017] Another aim of the present invention is to provide a pharmaceutical dosage form comprising the SGLT-2 inhibitor 1-chloro-4-(P-D-glucopyranos-1-yl)-2-[4-(('SJ-tetrahydrofuran-3-yloxy)-benzyl]-benzene and metformin hydrochloride which has an acceptable size.
[0018] Another aim of the invention is to provide a pharmaceutical dosage form comprising the SGLT-2 inhibitor 1-chloro-4-(p-D-glucopyranos-1-yl)-2-[4-((SJ-tetrahydrofuran-3-yloxy)-benzyl]-benzene and metformin hydrochloride which has a short disintegration time, which has good dissolution properties and/or which enables a high bioavailability of the SGLT-2 inhibitor in a patient.
[0019] Another aim of the invention it to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising the SGLT2 inhibitor 1-chloro-4-0-D-glucopyranos-1-yl)-2-[4-(fS)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and metformin, hydrochloride, and their use for preventing, slowing progression of, delaying or treating a metabolic disorder, in particular of type 2 diabetes mellitus.
[0020] A further aim of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising the SGLT2 inhibitor 1-chtoro-4-(p-D-glucopyranos-1-yl)-2-[4-((,Sj-tetrahydrofuran-3-yloxy)-benzyl]-benzene and metformin, hydrochloride, and their use for improving glyeemic control in a patient in need thereof, in particular in patients with type 2 diabetes mellitus.
[0021] Another aim of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising the SGLT2 inhibitor 1-chtoro-4-(P-D-glucopyranos-1-yl)-2-[4-(('S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and metformin, hydrochloride, and their use for improving glyeemic control in a patient with insufficient glyeemic control.
[0022] Another aim of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising the SGLT2 inhibitor 1-chtoro-4-(P-D-glucopyranos-1-yl)-2-[4-(('S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and metformin, hydrochloride, and their use for preventing, slowing or delaying progression from impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or metabolic syndrome to type 2 diabetes mellitus.
[0023] Yet another aim of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising the SGLT2 inhibitor 1-chtoro-4-(P-D-glucopyranos-1-yl)-2-[4-(/SJ-tetrahydrofuran-3-yloxy)-benzyl]-benzene and metformin, hydrochloride, and their use for preventing, slowing progression of, delaying or treating of a condition or disorder from the group consisting of complications of diabetes mellitus. Another aim of the present invention is to provide a pharmaceutical composition and a pharmaceutical dosage form, each comprising the SGLT2 inhibitor 1-chtoro-4-(P-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and metformin hydrochloride, with a high efficacy for the treatment of metabolic disorders, in particular of diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), and/or hyperglycemia, which has good to very good pharmacological and/or pharmacokinetic and/or physicochemical properties.
[0024] Further aims of the present invention become apparent to the one skilled in the art by description hereinbefore and in the following and by the examples.
Summary of the Invention [0025] In one aspect the present invention provides a solid pharmaceutical composition comprising the SGLT-2 inhibitor 1-chloro-4-(a-D-glucopyranos-1-yl)-2-[4-(/S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, metformin hydrochloride and one or more pharmaceutical excipients, wherein the SGLT-2 inhibitor is present in a dosage strength of 5 mg or 12.5 mg, and wherein metformin hydrochloride is present in a dosage strength of 500 mg, 850 mg or 1000 mg, and wherein the solid pharmaceutical composition comprises copovidone as a binder, for example a solid pharmaceutical composition for oral administration.
[0026] In general, pharmaceutical excipients which may be used may be selected from the group consisting of one or more fillers, one or more binders or diluents, one or more lubricants, one or more disintegrants, and one or more glidants, one or more filmcoating agents, one or more plasticizers, one or more pigments, and the like.
[0027] In more detail, the pharmaceutical compositions (tablets) of this invention comprise usually one or more fillers (e.g. D-mannitol, corn starch and/or pregelatinized starch and/or microcrystalline cellulose), a binder (copovidone), a lubricant (e.g. magnesium stearate, sodium stearyl fumarate), and a glidant (e.g. colloidal anhydrous silica).
[0028] Suitably the pharmaceutical excipients used within this invention are conventional materials such as D-mannitol, corn starch, microcrystalline cellulose, pregelatinized starch as a filler, copovidone as a binder, magnesium stearate or sodium stearyl fumarate as a lubricant, colloidal anhydrous silica as a glidant, hypromellose as a film-coating agent, propylene glycol as a plasticizer, titanium dioxide, iron oxide red/yellow/black or mixture thereof as a pigment, and talc, etc.
[0029] A typical composition according to the present invention comprises the binder copovidone (also known as copolyvidone or
Kollidon VA64).
[0030] A typical composition according to the present invention comprises the filler corn starch, the binder copovidone, the lubricant magnesium stearate, and the glidant colloidal anhydrous silica.
[0031] Further, a typical composition according to the present invention comprises the filler microcrystalline cellulose, the binder copovidone, the lubricant magnesium stearate or sodium stearyl fumarate, and the glidant colloidal anhydrous silica and optionally the disintegrant crospovidone or croscarmellose sodium.
[0032] Thus, in particular, the present invention is directed to a solid pharmaceutical composition (especially an oral solid dosage form, particularly a tablet) comprising the SGLT-2 inhibitor 1-chloro-4-(p-D-glucopyranos-1-yl)-2-[4-(/S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, metformin hydrochloride, wherein the SGLT-2 inhibitor is present in a dosage strength of 5 mg or 12.5 mg, and wherein metformin hydrochloride is present in a dosage strength of 500 mg, 850 mg or 1000 mg, and one or more pharmaceutical excipients, particularly one or more fillers, one or more binders, one or more glidants, and/or one or more lubricants, wherein the solid pharmaceutical composition comprises copovidone as a binder.
[0033] Typical pharmaceutical compositions of this invention may comprise in the SGLT-2 inhibitor portion (% by weight of total SGLT-2 inhibitor portion):
[0034] Typical pharmaceutical compositions of this invention may also comprise in the SGLT-2 inhibitor portion (% by weight of total SGLT-2 inhibitor portion):
[0035] Typical pharmaceutical compositions of this invention may comprise one or more of the following amounts (% by weight of total coated tablet mass):
[0036] Typical pharmaceutical compositions of this invention may comprise one or more of the following amounts (% by weight of total coated tablet mass):
[0037] In one embodiment, the FDC formulations are chemically stable and either a) display similarity of in-vitro dissolution profiles and/or are bioequivalent to the free combination, or b) allow to adjust the in-vitro and in-vivo performance to desired levels. In a preferred embodiment the invention relates to chemically stable FDC formulations maintaining the original dissolution profiles of corresponding mono tablets of each individual entity, with a reasonable tablet size.
[0038] In one embodiment, a pharmaceutical composition of this invention is produced using fluid bed granulation.
[0039] Further details about the FDC formulations of this invention, e.g. the ingredients, ratio of ingredients (such as e.g. ratio of the SGLT-2 inhibitor, metformin hydrochloride and/or excipients), particularly with respect to special dosage forms (tablets) used within this invention as well as their preparation, become apparent to the skilled person from the disclosure hereinbefore and hereinafter (including by way of example in the following examples).
[0040] The SGLT2 inhibitor according to this invention is the compound (1.9):
or a crystalline form (I.9X) of compound (1.9).
[0041] The pharmaceutical compositions according to the invention allow a high content uniformity and an effective production with regard to time and costs of pharmaceutical dosage forms, such as tablets and capsules. Furthermore, in one embodiment, these pharmaceutical dosage forms are in particular tablets.
[0042] Therefore in another aspect the present invention provides a solid pharmaceutical dosage form comprising a pharmaceutical composition according to the invention, for example a solid pharmaceutical dosage form for oral administration.
[0043] A process for the preparation of a pharmaceutical dosage form according to the invention comprises one or more granulation processes wherein the active pharmaceutical ingredient together with one or more excipients is granulated.
[0044] It can be found that a pharmaceutical composition comprising the SGLT2 inhibitor 1-chloro-4-(p-D-glucopyranos-1-yl)-2-^-((Sj-tetrahydrofuran-S-yloxyJ-benzyll-benzene and metformin hydrochloride as defined hereinafter can advantageously be used for preventing, slowing progression of, delaying or treating a metabolic disorder, in particular for improving glycemic control in patients. This opens up new therapeutic possibilities in the treatment and prevention of type 2 diabetes mellitus, overweight, obesity, complications of diabetes mellitus and of neighboring disease states.
[0045] Therefore, in a first aspect the present invention provides a pharmaceutical composition as defined hereinbefore and hereinafter for use a method for preventing, slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome in a patient in need thereof.
[0046] According to another aspect of the invention, there is provided a pharmaceutical composition as defined hereinbefore and hereinafter for use in a method for improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of glycosylated hemoglobin HbA1c in a patient in need thereof.
[0047] The pharmaceutical composition according to this invention may also have valuable disease-modifying properties with respect to diseases or conditions related to impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or metabolic syndrome.
[0048] According to another aspect of the invention, there is provided a pharmaceutical composition as defined hereinbefore and hereinafter for use in a method for preventing, slowing, delaying or reversing progression from impaired glucose tolerance (IGT), insulin resistance and/or from metabolic syndrome to type 2 diabetes mellitus in a patient in need thereof.
[0049] As by the use of a pharmaceutical composition according to this invention, an improvement of the glycemic control in patients in need thereof is obtainable, also those conditions and/or diseases related to or caused by an increased blood glucose level may be treated.
[0050] According to another aspect of the invention, there is provided a pharmaceutical composition as defined hereinbefore and hereinafter for use a method for preventing, slowing the progression of, delaying or treating of a condition or disorder selected from the group consisting of complications of diabetes mellitus such as cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischaemia, diabetic foot, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease, in a patient in need thereof. In particular one or more aspects of diabetic nephropathy such as hyperperfusion, proteinuria and albuminuria may be treated, their progression slowed or their onset delayed or prevented. The term "tissue ischaemia" particularly comprises diabetic macroangiopathy, diabetic microangiopathy, impaired wound healing and diabetic ulcer. The terms "micro- and macrovascular diseases" and "micro- and macrovascular complications" are used interchangeably in this application.
[0051] By the administration of a pharmaceutical composition according to this invention and due to the activity of the SGLT2 inhibitor excessive blood glucose levels are not converted to insoluble storage forms, like fat, but excreted through the urine of the patient. Therefore, no gain in weight or even a reduction in body weight is the result.
[0052] In a method for reducing body weight or preventing an increase in body weight or facilitating a reduction in body weight in a patient in need thereof a pharmaceutical composition or a pharmaceutical dosage form of the present invention is administered to the patient.
[0053] The pharmacological effect of the SGLT2 inhibitor in the pharmaceutical composition according to this invention is independent of insulin. Therefore, an improvement of the glycemic control is possible without an additional strain on the pancreatic beta cells. By an administration of a pharmaceutical composition according to this invention a beta-cell degeneration and a decline of beta-cell functionality such as for example apoptosis or necrosis of pancreatic beta cells can be delayed or prevented. Furthermore, the functionality of pancreatic cells can be improved or restored, and the number and size of pancreatic beta cells increased. It may be shown that the differentiation status and hyperplasia of pancreatic beta-cells disturbed by hyperglycemia can be normalized by treatment with a pharmaceutical composition according to this invention.
[0054] According to another aspect of the invention, there is provided a pharmaceutical composition for use in a method for preventing, slowing, delaying or treating the degeneration of pancreatic beta cells and/or the decline of the functionality of pancreatic beta cells and/or for use in improving and/or restoring the functionality of pancreatic beta cells and/or restoring the functionality of pancreatic insulin secretion in a patient in need thereof.
[0055] By the administration of a pharmaceutical composition according to the present invention, an abnormal accumulation of fat in the liver may be reduced or inhibited. Therefore, according to another aspect of the present invention, there is provided a pharmaceutical composition for use in preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat in a patient in need thereof. Diseases or conditions which are attributed to an abnormal accumulation of liver fat are particularly selected from the group consisting of general fatty liver, non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), hyperalimentation-induced fatty liver, diabetic fatty liver, alcoholic-induced fatty liver or toxic fatty liver.
[0056] As a result thereof, another aspect of the invention provides a pharmaceutical composition for use in a method for maintaining and/or improving the insulin sensitivity and/or for use in treating or preventing hyperinsulinemia and/or insulin resistance in a patient in need thereof.
Definitions [0057] The term "active ingredient" of a pharmaceutical composition according to the present invention means the SGLT2 inhibitor according to the present invention. An "active ingredient is also sometimes referred to herein as an "active substance".
[0058] The term "body mass index" or "ΒΜΓ of a human patient is defined as the weight in kilograms divided by the square of the height in meters, such that BMI has units of kg/m2 [0059] The term "overweight" is defined as the condition wherein the individual has a BMI greater than or 25 kg/m2 and less than 30 kg/m2. The terms "overweight" and "pre-obese" are used interchangeably.
[0060] The term "obesity" is defined as the condition wherein the individual has a BMI equal to or greater than 30 kg/m2. According to a WHO definition the term obesity may be categorized as follows: the term "class I obesity" is the condition wherein the BMI is equal to or greater than 30 kg/m2 but lower than 35 kg/m2; the term "class II obesity" is the condition wherein the BMI is equal to or greater than 35 kg/m2 but lower than 40 kg/m2; the term "class III obesity" is the condition wherein the BMI is equal to or greater than 40 kg/m2.
[0061] The term "visceral obesity" is defined as the condition wherein a waist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 in women is measured. It defines the risk for insulin resistance and the development of pre-diabetes.
[0062] The term "abdominal obesity" is usually defined as the condition wherein the waist circumference is > 40 inches or 102 cm in men, and is > 35 inches or 94 cm in women. With regard to a Japanese ethnicity or Japanese patients abdominal obesity may be defined as waist circumference £ 85 cm in men and > 90 cm in women (see e.g. investigating committee for the diagnosis of metabolic syndrome in Japan).
[0063] The term "euglycemia" is defined as the condition in which a subject has a fasting blood glucose concentration within the normal range, greater than 70 mg/dL (3.89 mmol/L) and less than 110 mg/dL (6.11 mmol/L). The word "fasting" has the usual meaning as a medical term.
[0064] The term "hyperglycemia" is defined as the condition in which a subject has a fasting blood glucose concentration above the normal range, greater than 110 mg/dL (6.11 mmol/L). The word "fasting" has the usual meaning as a medical term.
[0065] The term "hypoglycemia" is defined as the condition in which a subject has a blood glucose concentration below the normal range of 60 to 115 mg/dL (3.3 to 6.3 mmol/L).
[0066] The term "postprandial hyperglycemia" is defined as the condition in which a subject has a 2 hour postprandial blood glucose or serum glucose concentration greater than 200 mg/dL (11.11 mmol/L).
[0067] The term "impaired fasting blood glucose" or "IFG" is defined as the condition in which a subject has a fasting blood glucose concentration or fasting serum glucose concentration in a range from 100 to 125 mg/dl (i.e. from 5.6 to 6.9 mmol/l), in particular greater than 110 mg/dL and less than 126 mg/dl (7.00 mmol/L). A subject with "normal fasting glucose" has a fasting glucose concentration smaller than 100 mg/dl, i.e. smaller than 5.6 mmol/l.
[0068] The term "impaired glucose tolerance" or "IGT" is defined as the condition in which a subject has a 2 hour postprandial blood glucose or serum glucose concentration greater than 140 mg/dl (7.78 mmol/L) and less than 200 mg/dL (11.11 mmol/L). The abnormal glucose tolerance, i.e. the 2 hour postprandial blood glucose or serum glucose concentration can be measured as the blood sugar level in mg of glucose per dL of plasma 2 hours after taking 75 g of glucose after a fast. A subject with "normal glucose tolerance" has a 2 hour postprandial blood glucose or serum glucose concentration smaller than 140 mg/dl (7.78 mmol/L).
[0069] The term "hyperinsulinemia" is defined as the condition in which a subject with insulin resistance, with or without euglycemia, has fasting or postprandial serum or plasma insulin concentration elevated above that of normal, lean individuals without insulin resistance, having a waist-to-hip ratio <1.0 (for men) or < 0.8 (for women).
[0070] The terms "insulin-sensitizing", "insulin resistance-improving" or "insulin resistance-lowering" are synonymous and used interchangeably.
[0071] The term "insulin resistance" is defined as a state in which circulating insulin levels in excess of the normal response to a glucose load are required to maintain the euglycemic state (Ford ES, et al. JAMA. (2002) 287:356-9). A method of determining insulin resistance is the euglycaemic-hyperinsulinaemic clamp test. The ratio of insulin to glucose is determined within the scope of a combined insulin-glucose infusion technique. There is found to be insulin resistance if the glucose absorption is below the 25th percentile of the background population investigated (WHO definition). Rather less laborious than the clamp test are so called minimal models in which, during an intravenous glucose tolerance test, the insulin and glucose concentrations in the blood are measured at fixed time intervals and from these the insulin resistance is calculated. With this method, it is not possible to distinguish between hepatic and peripheral insulin resistance.
[0072] Furthermore, insulin resistance, the response of a patient with insulin resistance to therapy, insulin sensitivity and hyperinsulinemia may be quantified by assessing the "homeostasis model assessment to insulin resistance (HOMA-IR)" score, a reliable indicator of insulin resistance (Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Further reference is made to methods for the determination of the HOMA-index for insulin sensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), of the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl.1): A459) and to an euglycemic clamp study. In addition, plasma adiponectin levels can be monitored as a potential surrogate of insulin sensitivity. The estimate of insulin resistance by the homeostasis assessment model (HOMA)-IR score is calculated wth the formula (Galvin P, et al. Diabet Med 1992;9:921-8): HOMA-IR = [fasting serum insulin (pU/mL)] x [fasting plasma glucose(mmol/L)/22.5] [0073] As a rule, other parameters are used in everyday clinical practice to assess insulin resistance. Preferably, the patient's triglyceride concentration is used, for example, as increased triglyceride levels correlate significantly with the presence of insulin resistance.
[0074] Patients with a predisposition for the development of IGT or IFG or type 2 diabetes are those having euglycemia with hyperinsulinemia and are by definition, insulin resistant. A typical patient with insulin resistance is usually overweight or obese. If insulin resistance can be detected, this is a particularly strong indication of the presence of pre-diabetes. Thus, it may be that in order to maintain glucose homoeostasis a person needs 2-3 times as much insulin as a healthy person, without this resulting in any clinical symptoms.
[0075] The methods to investigate the function of pancreatic beta-cells are similar to the above methods with regard to insulin sensitivity, hyperinsulinemia or insulin resistance: An improvement of beta-cell function can be measured for example by determining a HOMA-index for beta-cell function (Matthews et al., Diabetologia 1985, 28: 412-19), the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl.1): A459), the insulin/C-peptide secretion after an oral glucose tolerance test or a meal tolerance test, or by employing a hyperglycemic clamp study and/or minimal modeling after a frequently sampled intravenous glucose tolerance test (Stumvoll et al., Eur J Clin Invest 2001, 31: 380-81J.
[0076] The term "pre-diabetes" is the condition wherein an individual is pre-disposed to the development of type 2 diabetes. Pre-diabetes extends the definition of impaired glucose tolerance to include individuals with a fasting blood glucose within the high normal range S 100 mg/dL (J. B. Meigs, et al. Diabetes 2003; 52:1475-1484) and fasting hyperinsulinemia (elevated plasma insulin concentration). The scientific and medical basis for identifying pre-diabetes as a serious health threat is laid out in a Position Statement entitled "The Prevention or Delay of Type 2 Diabetes" issued jointly by the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases (Diabetes Care 2002; 25:742-749).
[0077] Individuals likely to have insulin resistance are those who have two or more of the following attributes: 1) overweight or obese, 2) high blood pressure, 3) hyperlipidemia, 4) one or more 1st degree relative with a diagnosis of IGT or IFG or type 2 diabetes. Insulin resistance can be confirmed in these individuals by calculating the HOMA-IR score. For the purpose of this invention, insulin resistance is defined as the clinical condition in which an individual has a FIOMA-IR score > 4.0 or a HOMA-IR score above the upper limit of normal as defined for the laboratory performing the glucose and insulin assays.
[0078] The term "type 2 diabetes" is defined as the condition in which a subject has a fasting blood glucose or serum glucose concentration greater than 125 mg/dL (6.94 mmol/L). The measurement of blood glucose values is a standard procedure in routine medical analysis. If a glucose tolerance test is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hours after 75 g of glucose have been taken on an empty stomach. In a glucose tolerance test 75 g of glucose are administered orally to the patient being tested after 10-12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after taking it. In a healthy subject, the blood sugar level before taking the glucose will be between 60 and 110 mg per dL of plasma, less than 200 mg per dL 1 hour after taking the glucose and less than 140 mg per dL after 2 hours. If after 2 hours the value is between 140 and 200 mg, this is regarded as abnormal glucose tolerance.
[0079] The term "late stage type 2 diabetes mellitus" includes patients with a secondary drug failure, indication for insulin therapy and progression to micro- and macrovascular complications e.g. diabetic nephropathy, or coronary heart disease (CHD).
[0080] The term "HbA1c" refers to the product of a non-enzymatic glycation of the haemoglobin B chain. Its determination is well known to one skilled in the art. In monitoring the treatment of diabetes mellitus the HbA1c value is of exceptional importance. As its production depends essentially on the blood sugar level and the life of the erythrocytes, the HbA1c in the sense of a "blood sugar memory" reflects the average blood sugar levels of the preceding 4-6 weeks. Diabetic patients whose HbA1c value is consistently well adjusted by intensive diabetes treatment (i.e. <6.5 % of the total haemoglobin in the sample), are significantly better protected against diabetic microangiopathy. For example, metformin on its own achieves an average improvement in the FbA1 c value in the diabetic of the order of 1.0-1.5 %. This reduction of the HbA1c value is not sufficient in all diabetics to achieve the desired target range of < 6.5 % and preferably < 6 % FbA1c.
[0081] The term "insufficient glycemic control" or "inadequate glycemic control" in the scope of the present invention means a condition wherein patients show HbA1c values above 6.5 %, in particular above 7.0 %, even more preferably above 7.5 %, especially above 8 %.
[0082] The "metabolic syndrome", also called "syndrome X" (when used in the context of a metabolic disorder), also called the "dysmetabolic syndrome” is a syndrome complex with the cardinal feature being insulin resistance (Laaksonen DE, et al. Am J Epidemiol 2002; 156:1070-7). According to the ATP lll/NCEP guidelines (Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of high Blood Cholesterol in Adults (Adult Treatment Panel III) JAMA: Journal of the American Medical Association (2001) 285:2486-2497), diagnosis of the metabolic syndrome is made when three or more of the following risk factors are present: 1. 1. Abdominal obesity, defined as waist circumference > 40 inches or 102 cm in men, and > 35 inches or 94 cm in women; or with regard to a Japanese ethnicity or Japanese patients defined as waist circumference > 85 cm in men and > 90 cm in women;
2. 2. Triglycerides: £ 150 mg/dL 3. 3. HDL-cholesterol < 40 mg/dL in men 4. 4. Blood pressure £ 130/85 mm Hg (SBP £ 130 or DBP £ 85)
5. 5. Fasting blood glucose s 110 mg/dL
[0083] The NCEP definitions have been validated (Laaksonen DE, et al. Am J Epidemiol. (2002) 156:1070-7). Triglycerides and HDL cholesterol in the blood can also be determined by standard methods in medical analysis and are described for example in Thomas L (Editor): "Labor und Diagnose", TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.
[0084] According to a commonly used definition, hypertension is diagnosed if the systolic blood pressure (SBP) exceeds a value of 140 mm Hg and diastolic blood pressure (DBP) exceeds a value of 90 mm Hg. If a patient is suffering from manifest diabetes it is currently recommended that the systolic blood pressure be reduced to a level below 130 mm Hg and the diastolic blood pressure be lowered to below 80 mm Hg.
[0085] The term "SGLT2 inhibitor" in the scope of the present invention relates to compounds, in particular to glucopyranosyl-derivatives, i.e. compounds having a glucopyranosyl-moiety, which show an inhibitory effect on the sodium-glucose transporter 2 (SGLT2), in particular the human SGLT2. The inhibitory effect on hSGLT2 measured as IC50 is preferably below 1000 nM, even more preferably below 100 nM, most preferably below 50 nM. The inhibitory effect on hSGLT2 can be determined by methods known in the literature, in particular as described in the application WO 2005/092877 or WO 2007/093610 (pages 23/24), which are incorporated herein by reference in its entirety. The term "SGLT2 inhibitor” also comprises any pharmaceutically acceptable salts thereof, hydrates and solvates thereof, including the respective crystalline forms.
[0086] The terms "treatment" and "treating" comprise therapeutic treatment of patients having already developed said condition, in particular in manifest form. Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease. Thus the compositions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for chronic therapy.
[0087] The terms "prophylactically treating", "preventively treating” and "preventing” are used interchangeably and comprise a treatment of patients at risk to develop a condition mentioned hereinbefore, thus reducing said risk.
[0088] The term "tablet" comprises tablets without a coating and tablets with one or more coatings. Furthermore the term "tablet" comprises tablets having one, two, three or even more layers and press-coated tablets, wherein each of the before mentioned types of tablets may be without or with one or more coatings. The term "tablet" also comprises mini, melt, chewable, effervescent and orally disintegrating tablets.
[0089] The terms "pharmacopoe" and "pharmacopoeias" refer to standard pharmacopoeias such as the "USP 31-NF 26 through Second Supplement" (United States Pharmacopeial Convention) or the "European Pharmacopoeia 6.3" (European Directorate for the Quality of Medicines and Health Care, 2000-2009).
Detailed Description [0090] The aspects according to the present invention, in particular the pharmaceutical compositions and uses, refer to the SGLT2 inhibitor (1.9) 1-chloro-4-(p-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene
or a prodrug thereof.
[0091] Compounds of the formula (I)
and methods of their synthesis are described for example in the following patent applications: WO 2005/092877, WO 2006/117360, WO 2006/117359, WO 2006/120208, WO 2006/064033, WO 2007/031548, WO 2007/093610, WO 2008/020011, WO 2008/055870.
[0092] According to this invention, it is to be understood that the definition of (1.9) also comprises its hydrates, solvates and polymorphic forms thereof, and prodrugs thereof. An advantageous crystalline form of (1.9) is described in the international patent application WO 2006/117359. This crystalline form possesses good solubility properties which enable a good bioavailability of the SGLT2 inhibitor. Furthermore, the crystalline form is physico-chemically stable and thus provides a good shelf-life stability of the pharmaceutical composition.
[0093] A preferred crystalline form (I.9X) of the compound (1.9) can be characterized by an X-ray powder diffraction pattern that comprises peaks at 18.84, 20.36 and 25.21 degrees 2Θ (± 0.1 degrees 2Θ), wherein said X-ray powder diffraction pattern (XRPD) is made using CuKai radiation.
[0094] In particular said X-ray powder diffraction pattern comprises peaks at 14.69, 18.84, 19.16, 19.50, 20.36 and 25.21 degrees 2Θ (± 0.1 degrees 2Θ), wherein said X-ray powder diffraction pattern is made using CuKq-i radiation.
[0095] In particular said X-ray powder diffraction pattern comprises peaks at 14.69, 17.95, 18.43, 18.84, 19.16, 19.50, 20.36, 22.71, 23.44, 24.81, 25.21 and 25.65 degrees 20 (± 0.1 degrees 2Θ), wherein said X-ray powder diffraction pattern is made using CuK^ radiation.
[0096] More specifically, the crystalline form (I.9X) is characterised by an X-ray powder diffraction pattern, made using CuKa-| radiation, which comprises peaks at degrees 2Θ (± 0.1 degrees 20) as contained in Table 1.
Table 1: X-ray powder diffraction pattern of the crystalline form (I.9X) (only peaks up to 30° in 2 Θ are listed):
[0097] Even more specifically, the crystalline form (I.9X) is characterised by an X-ray powder diffraction pattern, made using CuKdi radiation, which comprises peaks at degrees 2Θ (±0.1 degrees 20)as shown in Figure 1 of WO 2006/117359.
[0098] Furthermore the crystalline form (I.9X) is characterised by a melting point of about 151°C ± 5°C (determined via DSC; evaluated as onset-temperature; heating rate 10 K/min). The obtained DSC curve is shown in Figure 2 of WO 2006/117359.
[0099] The X-ray powder diffraction patterns are recorded, within the scope of the present invention, using a STOE - STADI P-diffractometer in transmission mode fitted with a location-sensitive detector (OED) and a Cu-anode as X-ray source (CuKal radiation, λ = 1,54056 Å, 40 kV, 40 mA). In the Table 1 above the values "20 [°]" denote the angle of diffraction in degrees and the values "d [Å]" denote the specified distances in Å between the lattice planes. The intensity shown in the Figure 1 of WO 2006/117359 is given in units of cps (counts per second).
[0100] In order to allow for experimental error, the above described 20 values should be considered accurate to ± 0.1 degrees 20, in particular ± 0.05 degrees 20. That is to say, when assessing whether a given sample of crystals of the compound (1.9) is the crystalline form in accordance with the invention, a 20 value which is experimentally observed for the sample should be considered identical with a characteristic value described above if it falls within ± 0.1 degrees 20 of the characteristic value, in particular if it falls within ± 0.05 degrees 20 of the characteristic value.
[0101] The melting point is determined by DSC (Differential Scanning Calorimetry) using a DSC 821 (Mettler Toledo).
[0102] In one embodiment, a pharmaceutical composition or dosage form according to the present invention comprises the compound (1.9), wherein at least 50 % by weight of the compound (1.9) is in the form of its crystalline form (I.9X) as defined hereinbefore. Preferably in said composition or dosage form at least 80 % by weight, more preferably at least 90 % by weight of the compound (1.9) is in the form of its crystalline form (I.9X) as defined hereinbefore.
[0103] The oral administration is preferred. Particular dosage strengths for use in the present invention (e.g. per tablet or capsule) are 5 mg or 12.5 mg of the SGLT2 inhibitor (1.9) or its crystalline form (I.9X).
[0104] The partner drug to be combined with the SGLT-2 within the pharmaceutical compositions according to this invention is metformin hydrochloride (1,1-dimethylbiguanide hydrochloride or metformin HCI).
[0105] The biguanide antihyperglycemic agent metformin is disclosed in US patent No. 3,174,901.The preparation of metformin (dimethyldiguanide) and its hydrochloride salt is state of the art and was disclosed first by Emil A. Werner and James Bell, J. Chem. Soc. 121, 1922, 1790-1794.
[0106] Unit dosage strengths of metformin hydrochloride for incorporation into the fixed dose combination pharmaceutical compositions of the present invention are 500, 850 and 1000 mg of metformin hydrochloride.
[0107] In a further aspect of the present invention, a pharmaceutical composition, formulation, blend or dosage form of this invention is substantially free of or only marginally comprises impurities and/or degradation products; that means, for example, that the composition, formulation, blend or dosage from includes about <5%, or about <4%, or about <3%, or less than about 2%, preferably less than about 1%, more preferably less than about 0.5%, even more preferably less than about 0.2% of any individual or total impurity or degradation product(s) by total weight.
[0108] Dosage forms for the FDC formulations of this invention: [0109] Another purpose of this invention is to develop the FDC formulations of this invention with a reasonable tablet size, with good tablet properties (e g. stability, hardness, friability, disintegration, dissolution profile, content uniformity and the like).
[0110] Thus, it has been found that suitable dosage forms for the FDC formulations of this invention are film-coated tablets (filmcoating for drug loading, such as particularly SGLT-2 inhibitor drug loading by film coating on tablet cores containing the partner drug metformin hydrochloride), mono-layer tablets, bi-layer tablets, tri-layer tablets and press-coated tablets (e.g. tablet-in-tablet or bull's eye tablet with SGLT-2 inhibitor core), which dosage forms are good measures to achieve the goal under consideration of desired pharmaceutical profiles and characteristics of the SGLT-2 inhibitor 1-chloro-4-(P-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzBne and the partner drug metformin hydrochloride. Said dosage forms have been found to be applicable to the FDC formulations either keeping the original dissolution profiles of each mono tablet or adjusting the profiles to desired levels, and a reasonable tablet size.
[0111] Atypical mono-layer tablet of this invention comprises the SGLT-2 inhibitor 1-chtoro-4-(p-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, metformin hydrochloride, one or more fillers (such as e.g. corn starch), one or more binders (such as e.g. copovidone), one or more glidants (such as e.g. colloidal anhydrous silica) and one or more lubricants (such as e.g. magnesium stearate).
[0112] In one embodiment of the present invention, the present invention is directed to an oral solid pharmaceutical composition, preferably a tablet, particularly a mono-layer tablet, wherein one or more of the following applies: • the percentage of metformin hydrochloride is about 84 % by weight of total tablet core, • the percentage of the SGLT-2 inhibitor is about 0.1 %- 2.12%, e.g. 0.1 %- 2.11% by weight of total tablet core, • the tablet crushing strength is higher than or equal 100 N, • the tablet friability is lower than or equal 0.5 %, • the tablet core weight is from about 560 to about 1180 mg, and • the tablet disintegration time is lower than or equal 15 min.
[0113] In a preferred embodiment of the present invention, the present invention is directed to an oral solid pharmaceutical composition, preferably a tablet, particularly a mono-layer tablet comprising or made from the compound of the formula (1.9) or its crystalline form (I.9X), in an amount of 5 or 12.5 mg, metformin hydrochloride in an amount of 500 mg, 850 mg or 1000 mg, and one or more pharmaceutical excipients, particularly one or more fillers (e.g. corn starch), one or more binders (e.g. copovidone), one or more glidants (e.g. colloidal anhydrous silica) and/or one or more lubricants (e.g. magnesium stearate), as well as, optionally, a film coat e.g. comprising one or more film-coating agents (e.g. hypromellose), one or more plasticizers (e.g. propylene glycol, polyethylene glycol or triethyl citrate), one or more pigments (e.g. titanium dioxide, iron oxide red/yellow/black or mixture thereof) and/or one or more glidants (e.g. talc).
[0114] A method of manufacturing a tablet of this invention comprises tabletting (e g. compression) of one or more final blends in form of granules. Granules of the (final) blend(s) according to this invention may be prepared by methods well-known to one skilled in the art (e.g. high shear wet granulation or fluid bed granulation). Granules according to this invention as well as details of granulation processes (including their separate steps) for the preparation of granules of this invention are described by way of example in the following examples.
[0115] An illustrative granulation process for the preparation of granules comprising the mono-layer composition comprises 1. i.) combining (e.g. dissolving or dispersing) a binder (e.g. copovidone) and, optionally, the SGLT-2 inhibitor of the formula (1.9) or its crystalline form (I.9X) in a solvent or mixture of solvents such as purified water at ambient temperature to produce a granulation liquid; 2. ii.) blending metformin HCI, a filler (e.g. corn starch) and, optionally, the SGLT-2 inhibitor in a suitable mixer (e.g. fluid-bed granulator) to produce a pre-mix; wherein the SGLT-2 inhibitor may be included either in the granulation liquid obtained in i.) or in the pre-mix obtained in ii.), preferably the SGLT-2 inhibitor is dispersed in the granulation liquid and is absent in the pre-mix; 3. iii.) spraying the granulation-liquid into the pre-mix and granulating the mixture for example in a fluid-bed granulator, preferably under dry condition; 4. iv.) drying the granulate, e.g. at about 70° C inlet air temperature until the desired loss on drying value in the range of 1-3 %, for example 0.8-2 %, is obtained; 5. v.) delumping the dried granulate for example by sieving through a sieve with a mesh size of 0.5 to 1.0 mm; 6. vi.) blending the sieved granulate and preferably sieved glidant (e.g. colloidal anhydrous silica) in a suitable blender; 7. vii.) adding preferably sieved lubricant (e.g. magnesium stearate) to the granulate for final blending for example in the free-fall blender.
[0116] Preferentially, a mono-layer tablet according to this invention comprises or is obtainable from a mixture comprising the SGLT-2 inhibitor and metformin hydrochloride.
[0117] A typical bi-layer tablet of this invention comprises a SGLT-2 inhibitor portion comprising the SGLT-2 inhibitor, one or more fillers (such as e.g. D-mannitol, pregelatinized starch and corn starch), one or more binders (such as e.g. copovidone) and one or more lubricants (such as e.g. magnesium stearate), and a metformin HCI portion comprising metformin hydrochloride, one or more fillers (such as e.g. corn starch), one or more binders (such as e.g. copovidone), one or more glidants (such as e.g. colloidal anhydrous silica) and one or more lubricants (such as e.g. magnesium stearate).
[0118] Atypical press-coated tablet (tablet-in-tablet or bull's eye tablet) of this invention comprises a SGLT-2 inhibitor core portion comprising the SGLT-2 inhibitor, one or more fillers (such as e.g. D-mannitol, pregelatinized starch and corn starch), one or more binders (such as e.g. copovidone) and one or more lubricants (such as e.g. magnesium stearate), and a metformin HCI portion comprising metformin hydrochloride, one or more fillers (such as e.g. corn starch), one or more binders (such as e.g. copovidone), one or more glidants (such as e.g. colloidal anhydrous silica) and one or more lubricants (such as e.g. magnesium stearate).
[0119] A typical film-coated tablet (the SGLT-2 inhibitor coating on metformin HCI tablet, i.e. drug layering by film-coating for drug loading) of this invention comprises a metformin HCI core portion comprising metformin hydrochloride, one or more fillers (such as e.g. corn starch), one or more binders (such as e.g. copovidone), one or more glidants (such as e.g. colloidal anhydrous silica) and one or more lubricants (such as e.g. magnesium stearate), wherein said core portion is seal-coated with a film coat comprising one or more film-coating agents (such as e.g. hypromellose), one or more plasticizers (such as e.g. propylene glycol, Macrogol 400, Macrogol 6000, Macrogol 8000), one or more pigments (such as e.g. titanium dioxide, iron oxide red/yellow/black or mixture thereof) and one or more glidants (such as e.g. talc); and a SGLT-2 inhibitor layer comprising the SGLT-2 inhibitor, one or more film-coating agents (such as e.g. hypromellose) and one or more plasticizers (such as e.g. propylene glycol, Macrogol 400, Macrogol 6000, or Macrogol 8000, triethyl citrate).
[0120] Another typical film-coated tablet (the SGLT-2 inhibitor coating on metformin HCI tablet, i.e. drug layering by film-coating for drug loading) of this invention comprises a metformin HCI core portion comprising metformin hydrochloride, one or more fillers (such as e.g. corn starch), one or more binders (such as e.g. copovidone), one or more glidants (such as e.g. colloidal anhydrous silica) and one or more lubricants (such as e.g. magnesium stearate), wherein said core portion is seal-coated with a film coat comprising one or more film-coating agents (such as e.g. hypromellose), one or more plasticizers (such as e.g. propylene glycol, Macrogol 400, Macrogol 6000, or Macrogol 8000, triethyl citrate), one or more pigments (such as e.g. titanium dioxide, iron oxide red/yellow/black or mixture thereof) and one or more glidants (such as e.g. talc); and a SGLT-2 inhibitor layer comprising the SGLT-2 inhibitor, one or more film-coating agents (such as e.g. hypromellose) and one or more plasticizers (such as e.g. propylene glycol, Macrogol 400, Macrogol 6000, or Macrogol 8000, triethyl citrate).
[0121] Preferably, these abovementioned tablets (mono-, bi-layer, press-coated and drug-coated tablets) are further overcoated with a final film coat, which comprises a film-coating agent (such as e.g. hypromellose), a plasticizer (such as e.g. propylene glycol, Macrogol 400, Macrogol 6000, or Macrogol 8000, triethyl citrate), pigments (such as e.g. titanium dioxide, iron oxide red/yellow/black or mixture thereof) and a glidant (such as e.g. talc). Typically this additional film over-coat may represent 1-4 %, preferentially 1-2 %, of the total mass of the composition.
[0122] A pharmaceutical composition or dosage form according to the present invention may be an immediate release pharmaceutical composition or dosage form, or a time-release pharmaceutical composition or dosage form.
[0123] Pharmaceutical immediate release dosage forms of this invention preferably have dissolution properties such that after 45 minutes for each of the active ingredients at least 75 %, even more preferably at least 90 % by weight of the respective active ingredient is dissolved. In a particular embodiment, after 30 minutes for each of the active ingredients especially of the mono-layer tablet according to this invention (including tablet core and film-coated tablet) at least 70-75 % (preferably at least 80 %) by weight of the respective active ingredient is dissolved. In a further embodiment, after 15 minutes for each of the active ingredients especially of the mono-layer tablet according to this invention (including tablet core and film-coated tablet) at least 55-60 % by weight of the respective active ingredient is dissolved. The dissolution properties can be determined in standard dissolution tests, e.g. according to standard pharmacopeias (e.g. using paddle method with agitation speed of 50 or 75 or 100 rpm, dissolution medium pH 6.8 at a temperature of 37°C).
[0124] A time-release dosage form refers to a formula that is not an immediate release dosage form. In a time-release dosage form the relase of the active ingredient is slow and occurs over time. Time-release dosage forms are also knowi as sustained-release (SR), sustained-action (SA), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), modified release (MR), or continuous-release (CR or Contin). In one aspect, a time-release dosage form may be a bi-layer tablet in which one or more of the active ingredients is released slowly. In one aspect, in a pharmaceutical composition and pharmaceutical dosage form according to the invention the SGLT-2 inhibitor of the formula (I.9) or its crystalline form (I.9X), or the partner drug metformin hydrochloride, is time-release.
[0125] In another aspect, in a pharmaceutical composition and pharmaceutical dosage form according to the invention the SGLT-2 inhibitor of the formula (I.9) or its crystalline form (I.9X), and the partner drug metformin hydrochloride, are time-release.
[0126] In the pharmaceutical compositions and pharmaceutical dosage forms according to the invention the SGLT-2 inhibitor of the formula (1.9) or its crystalline form (I.9X), preferably has a particle size distribution (preferably by volume) such that at least 90 % of the respective active pharmaceutical ingredient has a particle size smaller than 200 pm, i.e. X90 < 200 pm, more preferably X90 £ 150 pm. More preferably the particle size distribution is such that X90 < 100 pm, more preferably X90 £ 90 pm, even more preferably X90 £ 75 pm. In addition the particle size distribution is preferably such that X90 > 1 pm, more preferably X90 > 5 pm, most preferably X90 s 10 pm. Therefore preferred particle size distributions are such that 1 pm < X90 < 200 pm, particularly 1 pm < X90 £150 pm, more preferably 5 pm £ X90 £ 150 pm, even more preferably 5 pm < X90 <100 pm, even more preferably 10 pm < X90 £ 100 pm. A preferred example of a particle size distribution of the SGLT-2 inhibitor is 20 pm< X90 < 50 pm. It can be found that a pharmaceutical composition comprising compound (1.9), or crystalline form (I.9X) of compound (I.9) with a particle size distribution as indicated hereinbefore shows desired properties (e.g. with regard to dissolution, content uniformity, production, or the like). The indicated particle size properties are determined by laser-diffraction method, in particular low angle laser light scattering, i.e. Fraunhofer diffraction. Alternatively, the particle size properties can be also determined by microscopy (e.g. electron microscopy or scanning electron microscopy). The results of the particle size distribution determined by different techniques can be correlated with one another.
[0127] Optimized formulation of metformin HCI portion: [0128] Another purpose of this invention is to provide improved formulations of the metformin HCI portion of the pharmaceutical compositions according to this invention.
[0129] For the metformin HCI part a high drug load is advantageous to be achieved as a prerequisite for a reasonable small tablet size.
[0130] Thus, it has been found that drug load of metformin HCI and compactability (compression force-crushing strength profile) of the tablets of this invention can be improved by surface treatment of metformin HCI with a water-soluble polymer, particularly copolyvidone.
[0131] Several water-soluble polymers including polyvinyl alcohol (PVA), hypromellose (HPMC), hydroxypropyl cellulose (l-PC), methyl cellulose (MC), Povidone (PVP) and copolyvidone may be tested to improve compactability (compression force-crushing strength profile). As the results, PVA shows the best effect in terms of compactability but the manufacturability can be poor due to sticking problem during fluid-bed granulation. Further on, PVA may be not finally selected because of its negative impact on the stability of the SGLT-2 inhibitor of this invention.
[0132] Formulation optimization studies have identified a composition with over 83% drug load of metformin HCI and improved crushing strength by surface-treatment of metformin HCI with the water-soluble polymer copolyvidone.
[0133] Therefore, finally, copolyvidone is selected and advantageously resulting in stable formulations and the viscosity of the granulating solution is enough low to prepare the aqueous solution and operate spraying by a fluid-bed granulator.
[0134] When this invention refers to patients requiring treatment or prevention, it relates primarily to treatment and prevention in humans, but the pharmaceutical composition may also be used accordingly in veterinary medicine in mammals. In the scope of this invention adult patients are preferably humans of the age of 18 years or older.
[0135] As described hereinbefore by the administration of the pharmaceutical composition according to this invention and in particular in view of the high SGLT2 inhibitory activity of the SGLT2 inhibitor 1-chloro-4-(P-D-glucopyranos-1-yl)-2-[4-( (S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene therein, excessive blood glucose is excreted through the urine of the patient, so that no gain in weight or even a reduction in body weight may result. Therefore, a treatment or prophylaxis according to this invention is advantageously suitable in those patients in need of such treatment or prophylaxis who are diagnosed of one or more of the conditions selected from the group consisting of overweight and obesity, in particular class I obesity, class II obesity, class III obesity, visceral obesity and abdominal obesity. In addition a treatment or prophylaxis according to this invention is advantageously suitable in those patients in which a weight increase is contraindicated. The pharmaceutical composition as well as their uses according to the present invention allow a reduction of the FbA1 c value to a desired target range, for example < 7 % and preferably < 6.5 %, for a higher number of patients and for a longer time of therapeutic treatment compared with a corresponding monotherapy.
[0136] The pharmaceutical composition according to this invention and in particular the SGLT2 inhibitor 1-chloro-4-(P-D-glucopyranos-1-yl)-2-[4-((SJ-tetrahydrofuran-3-yloxy)-benzyl]-benzene therein exhibits a very good efficacy with regard to glycemic control, in particular in view of a reduction of fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin (HbA1c). By administering a pharmaceutical composition according to this invention, a reduction of HbA1c equal to or greater than preferably 0.5 %, even more preferably equal to or greater than 1.0 % can be achieved and the reduction is particularly in the range from 1.0 % to 2.0 %.
[0137] Furthermore, the use according to this invention is advantageously applicable in those patients who show one, two or more of the following conditions: 1. (a) a fasting blood glucose or serum glucose concentration greater than 110 mg/dL, in particular greater than 125 mg/dL; 2. (b) a postprandial plasma glucose equal to or greater than 140 mg/dL; 3. (c) an HbA1c value equal to or greater than 6.5 %, in particular equal to or greater than 7.0 %, especially equal to or greater than 7.5 %, even more particularly equal to or greater than 8.0 %.
[0138] The present invention also discloses the use of the pharmaceutical composition for improving glycemic control in patients having type 2 diabetes or showing first signs of pre-diabetes. Thus, the invention also includes diabetes prevention. If therefore a pharmaceutical composition according to this invention is used to improve the glycemic control as soon as one of the above-mentioned signs of pre-diabetes is present, the onset of manifest type 2 diabetes mellitus can be delayed or prevented.
[0139] Furthermore, the pharmaceutical composition according to this invention is particularly suitable in the treatment of patients with insulin dependency, i.e. in patients who are treated or otherwise would be treated or need treatment with an insulin or a derivative of insulin or a substitute of insulin or a formulation comprising an insulin or a derivative or substitute thereof. These patients include patients with diabetes type 2 and patients with diabetes type 1.
[0140] According to another preferred embodiment of the present invention, there is provided a use of the pharmaceutical composition in a method for improving glycemic control in patients, in particular in adult patients, with type 2 diabetes mellitus as an adjunct to diet and exercise.
[0141] Therefore, the use according to this invention is advantageously applicable in those patients who show one, two or more of the following conditions: 1. (a) insufficient glycemic control with diet and exercise alone; 2. (b) insufficient glycemic control despite oral monotherapy with metformin, in particular despite oral monotherapy at a maximal tolerated dose of metformin; 3. (c) insufficient glycemic control despite oral monotherapy with another antidiabetic agent, in particular despite oral monotherapy at a maximal tolerated dose of the other antidiabetic agent.
[0142] The lowering of the blood glucose level by the administration of the SGLT2 inhibitor 1-chloro-4-(3-D-glucopyranos-1-yl)-2-[4-(('SJ-tetrahydrofuran-3-yloxy)-benzyl]-benzene is insulin-independent. Therefore, a pharmaceutical composition according to this invention is particularly suitable in the treatment of patients who are diagnosed having one or more of the following conditions • insulin resistance, • hyperinsulinemia, • pre-diabetes, • type 2 diabetes mellitus, particular having a late stage type 2 diabetes mellitus, • type 1 diabetes mellitus.
[0143] Furthermore, a pharmaceutical composition according to this invention is particularly suitable in the treatment of patients who are diagnosed having one or more of the following conditions 1. (a) obesity (including class I, II and/or III obesity), visceral obesity and/or abdominal obesity, 2. (b) triglyceride blood level > 150 mg/dL, 3. (c) HDL-cholesterol blood level < 40 mg/dL in female patients and < 50 mg/dL in male patients, 4. (d) a systolic blood pressure >130 mm Hg and a diastolic blood pressure > 85 mm Hg, 5. (e) a fasting blood glucose level >110 mg/dL.
[0144] It is assumed that patients diagnosed with impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), with insulin resistance and/or with metabolic syndrome suffer from an increased risk of developing a cardiovascular disease, such as for example myocardial infarction, coronary heart disease, heart insufficiency, thromboembolic events. A glycemic control according to this invention may result in a reduction of the cardiovascular risks.
[0145] A pharmaceutical composition according to this invention exhibits a good safety profile. Therefore, a use according to this invention is advantageously possible in those patients for which the mono-therapy with another antidiabetic drug, such as for example metformin, is contraindicated and/or who have an intolerance against such drugs at therapeutic doses. In particular, a use according to this invention may be advantageously possible in those patients showing or having an increased risk for one or more of the following disorders: renal insufficiency or diseases, cardiac diseases, cardiac failure, hepatic diseases, pulmonal diseases, catabolytic states and/or danger of lactate acidosis, or female patients being pregnant or during lactation.
[0146] Furthermore, it can be found that the administration of a pharmaceutical composition according to this invention results in no risk or in a low risk of hypoglycemia. Therefore, a use according to this invention is also advantageously possible in those patients showing or having an increased risk for hypoglycemia.
[0147] A pharmaceutical composition according to this invention is particularly suitable in the long term treatment or prophylaxis of the diseases and/or conditions as described hereinbefore and hereinafter, in particular in the long term glycemic control in patients with type 2 diabetes mellitus.
[0148] The term "long term" as used hereinbefore and hereinafter indicates a treatment of or administration in a patient within a period of time longer than 12 weeks, preferably longer than 25 weeks, even more preferably longer than 1 year.
[0149] Therefore, a particularly preferred embodiment of the present invention provides a use in a method for therapy, preferably oral therapy, for improvement, especially long term improvement, of glycemic control in patients with type 2 diabetes mellitus, especially in patients with late stage type 2 diabetes mellitus, in particular in patients additionally diagnosed of overweight, obesity (including class I, class II and/or class III obesity), visceral obesity and/or abdominal obesity.
[0150] It will be appreciated that the amount of the pharmaceutical composition according to this invention to be administered to the patient and required for use in treatment or prophylaxis according to the present invention will vary with the route of administration, the nature and severity of the condition for which treatment or prophylaxis is required, the age, weight and condition of the patient, concomitant medication and will be ultimately at the discretion of the attendant physician. In general, however, the SGLT2 inhibitor 1-chioro-4-(P-D-giucopyranos-1-yl)-2-[4-( (S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and metformin hydrochloride according to this invention is included in the pharmaceutical composition or dosage form in an amount sufficient that by its administration the glycemic control in the patient to be treated is improved.
[0151] In the following preferred ranges of the amount of the SGLT2 inhibitor 1-chioro-4-(P-D-glucopyranos-1-yl)-2-[4-(('S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and metformin, hydrochloride to be employed in the pharmaceutical composition and the uses according to this invention are described. These ranges refer to the amounts to be administered per day with respect to an adult patient, in particular to a human being, for example of approximately 70 kg body weight, and can be adapted accordingly with regard to an administration 2, 3,4 or more times daily and with regard to other routes of administration and with regard to the age of the patient.
[0152] Within the scope of the present invention, the pharmaceutical composition is preferably administered orally. Other forms of administration are possible and described hereinafter. Preferably the one or more dosage forms comprising the SGLT2 inhibitor 1-chioro-4-(p-D-glucopyranos-1-yl)-2-[4-(('SJ-tetrahydrofuran-3-yloxy)-benzyl]-benzene and metformin, hydrochloride are oral or usually well known.
[0153] According to an embodiment a manufacture comprises (a) a pharmaceutical composition according to the present invention and (b) a label or package insert which comprises instructions that the medicament is to be administered.
[0154] The desired dose of the pharmaceutical composition according to this invention may conveniently be presented in a once daily or as divided dose administered at appropriate intervals, for example as two, three or more doses per day.
[0155] The pharmaceutical composition may be formulated for oral administration in solid form. Oral administration is preferred. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with one or more pharmaceutically acceptable carriers, like liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.
[0156] The pharmaceutical composition may be formulated in the form of tablets or capsules, caplets, soft capsules, pills, chewable tablets, troches, effervescent tablets, fast dissolving tablets, oral fast-dispersing tablets, etc..
[0157] The pharmaceutical composition and the dosage forms preferably comprise one or more pharmaceutical acceptable carriers which must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Examples of pharmaceutically acceptable carriers are known to the one skilled in the art.
[0158] Pharmaceutical compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, including soft gelatin capsules, or tablets each containing a predetermined amount of the active ingredient. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art.
[0159] The pharmaceutical compositions and methods according to this invention show advantageous effects in the treatment and prevention of those diseases and conditions as described hereinbefore. Advantageous effects may be seen for example with respect to efficacy, dosage strength, dosage frequency, pharmacodynamic properties, pharmacokinetic properties, fewer adverse effects, convenience, compliance, etc..
[0160] Methods for the manufacture of the SGLT2 inhibitor according to this invention and of prodrugs thereof are known to the one skilled in the art. Advantageously, the compound according to this invention can be prepared using synthetic methods as described in the literature, including patent applications as cited hereinbefore. Preferred methods of manufacture are described in the WO 2006/120208. An advantageous crystalline form is described in the international patent application WO 2006/117359 which hereby is incorporated herein in its entirety.
[0161] The active ingredients or a pharmaceutically acceptable salt thereof may be present in the form of a solvate such as a hydrate or alcohol adduct.
[0162] Any of the above mentioned pharmaceutical compositions and methods within the scope of the invention may be tested by animal models known in the art. In the following, in vivo experiments are described which are suitable to evaluate pharmacologically relevant properties of pharmaceutical compositions and methods according to this invention.
[0163] Pharmaceutical compositions and methods according to this invention can be tested in genetically hyperinsulinemic or diabetic animals like db/db mice, ob/ob mice, Zucker Fatty (fa/fa) rats or Zucker Diabetic Fatty (ZDF) rats. In addition, they can be tested in animals with experimentally induced diabetes like HanWistar or Sprague Dawley rats pretreated with streptozotocin.
[0164] The effect on glycemic control according to this invention can be tested after single dosing in an oral glucose tolerance test in the animal models described hereinbefore. The time course of blood glucose is followed after an oral glucose challenge in overnight fasted animals. The pharmaceutical compositions according to the present invention significantly improve glucose excursion, for example compared to another monotherapy, as measured by reduction of peak glucose concentrations or reduction of glucose AUC. In addition, after multiple dosing in the animal models described hereinbefore, the effect on glycemic control can be determined by measuring the HbA1c value in blood. The pharmaceutical compositions according to this invention significantly reduce HbA1c, for example compared to another monotherapy or compared to a dual-combination therapy.
[0165] The improved independence from insulin of the treatment according to this invention can be shown after single dosing in oral glucose tolerance tests in the animal models described hereinbefore. The time course of plasma insulin is followed after a glucose challenge in overnight fasted animals.
[0166] The increase in active GLP-1 levels by treatment according to this invention after single or multiple dosing can be determined by measuring those levels in the plasma of animal models described hereinbefore in either the fasting or postprandial state. Likewise, a reduction in glucagon levels in plasma can be measured under the same conditions.
[0167] The effect of the SGLT2 inhibitor 1-chloro-4-(P-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and metformin hydrochloride according to the present invention on beta-cell regeneration and neogenesis can be determined after multiple dosing in the animal models described hereinbefore by measuring the increase in pancreatic insulin content, or by measuring increased beta-cell mass by morphometric analysis after immunhistochemical staining of pancreatic sections, or by measuring increased glucose-stimulated insulin secretion in isolated pancreatic islets.
[0168] The present invention is not to be limited in scope by the specific embodiments described herein. Various modifications of the invention in addition to those described herein may become apparent to those skilled in the art from the present disclosure. Such modifications are intended to fall within the scope of the appended claims.
[0169] Further embodiments, features and advantages of the present invention may become apparent from the following examples. The following examples serve to illustrate, by way of example, the principles of the invention without restricting it.
Examples 1. Mono-layer Tablet [0170] Examples of the composition of mono-layer tablets for the SGLT-2 inhibitor of this invention (compound (1.9), or a crystalline form (I.9X) of compound (1.9)) + metformin HCI FDC (Film-coated Tablets) are shown in Tables 1.1 to 1.11.
[0171] Note: The film-coated tablets with a dosage strength of 1.25 mg with regard to (1.9), as presented in Tables 1.7 to 1.9, are not part of the claimed invention.
Table 1.1: Examples of composition of SGLT-2 inhibitor + Metformin HCI FDC Mono-layer Tablets
Table 1.11: Examples of composition of SGLT-2 inhibitor + Metformin HCI FDC Mono-layer
Tablets
[0172] Abroad dose range of the SGLT-2 inhibitor 1-chloro-4-(p-D-glucopyranos-1-yl)-2-[4-( fSJ-tetrahydrofuran-3-yloxy)-benzyl]-benzene, e g. 5 or 12.5 mg, could be used, in which case the amount of binder corn starch or microcrystalline cellulose is adjusted. Instead of corn starch, microcrystalline cellulose could be used. In the further description of the manufacturing procedure only corn starch is described.
Manufacturing procedure (Mono-layer tablets): [0173] The SGLT-2 inhibitor of this invention (compound (I.9), or crystalline form (I.9X) of compound (1.9)) + metformin HCI FDC mono-layer tablets are produced by a fluid-bed granulation process and a conventional tableting process with a rotary press. Metformin HCI and corn starch, the SGLT-2 inhibitor is either added as powder and premixed before fluid-bed granulation is conducted by spraying of "Granulation Liquid" composed of copolyvidon (Kollidon VA64 and purified water, or directly dispersed in the "granulation liquid". Alternatively, the SGLT-2 inhibitor is added as powder together with metformin-HCI and corn starch to the fluid bed granulator. After finishing of fluid-bed granulation, the granulate is sieved with a suitable screen. The sieved granulate is blended with colloidal anhydrous silica (Aerosil 200) and magnesium stearate as a lubricant. The final mixture is compressed into tablets using a conventional rotary tablet press.
[0174] The tablet cores may be film-coated by an aqueous film-coating suspension, containing hypromellose as film-forming agent, propylene glycol as plasticizer, talc as glidant and the pigments black, red, yellow iron oxide and mixture of red/yellow/black and titanium dioxide.
[0175] Narrative more specific description of the preferred manufacturing process for the mono-layer tablets: 1. a) Metformin HCI and corn starch are sieved using a screen with a mesh size of 0.5 to1 mm before dispensing. 2. b) Compound (I.9), or crystalline form (I.9X) of compound (I.9) and finally copolyvidon are dissolved resp. dispersed in purified water at ambient temperature with a propeller mixer to produce the "Granulation Liquid". 3. c) Metformin HCI and corn starch are sucked into a chamber of a suitable fluid-bed granulator and preheated up to a product temperature target of approx. 36°C. Preheating is optionally. Alternatively, the compound (I.9), or crystalline form (I.9X) of compound (I.9) and metformin-HCI and corn starch are sucked into a chamber of suitable fluid-bed granulator. 4. d) Immediately after the product temperature target is reached, the "Granulation Liquid" is sprayed into the mixture for fluid-bed granulating under dry condition to avoid blocking during granulation. 5. e) At the end of spraying, the resultant granulate is dried at approx 70 C inlet air temperature until the desired LOD value (i.e. 1 - 3 %, for example 0 8-2%) is reached. 6. f) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0 mm. 7. g) The sieved granulate and colloidal anhydrous silica (Aerosil 200) are blended with a suitable blender. Aerosil 200 should be pre-sieved with a small portion of the sieved granulate through a 0.8 mm-screen before use. 8. h) Magnesium stearate is passed through a 0.8 mm sieve and added into the granulate. Subsequently the “Final Blend" is produced by final blending in the free-fall blender. 9. i) The "Final Blend" is compressed into tablets with a rotary press. 10. j) Titanium dioxide, polyethylene glycol or propylene glycol and iron oxide (yellow, red, black or mixture thereof) are dispersed in purified water with a high shear homo-mixer. Then, hypromellose and talc are added and dispersed with a homo-mixer and propeller mixer at ambient temperature to produce the "Coating Suspension". 11. k) The tablet cores are coated with the "Coating Suspension" to the target weight gain to produce the “Film-coated
Tablets". The "Coating Suspension" should be stirred again before use and kept stirring slowly during the coating (spraying) process.
[0176] Narrative more specific description of an alternative manufacturing process for the mono-layer tablets: 1. a) Metformin HCI is sieved using a screen with a mesh size of 0.5 to1 mm before weighing. 2. b) copolyvidon are dissolved in purified water at ambient temperature with a propeller mixer to produce the “Granulation
Liquid" 3. c) is added into the container, then blended with metformin HCI and corn starch in the fluid-bed granulator. 4. d) The "Granulation Liquid" is sprayed into the mixture for fluid-bed granulating under dry condition to avoid blocking during granulation. 5. e) At the end of spraying, the resultant granulate is dried at 70 - 80 °C until the desired LOD value (i.e. 1 - 3 %, for example 0.8-2%), in case the LOD is more than 2 %. 6. f) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0 mm. 7. g) The sieved granulate and colloidal anhydrous silica (Aerosil 200) are blended with a suitable blender. Aerosil 200 should be sieved with a 0.5 mm-screen before use. 8. h) Magnesium stearate passed through a 0.5 mm sieve and added into the granulate. Subsequently the "Final Blend" is produced by final blending in the blender. 9. i) The "Final Blend” is compressed into tablets with a rotary press. 10. j) Hypromellose and polyethylene glycol or propylene glycol are dissolved in purified water with a propeller mixer. Talc, titanium dioxide, and iron oxide (yellow, red and/or black and mixture thereof) are dispersed in purified water with a homomixer. The suspension is added into the hypromellose solution, then mixed with a propeller mixer at ambient temperature to produce the "Coating Suspension". 11. k) The tablet cores are coated with the "Coating Suspension" to the target weight gain to produce the “Film-coated Tablets". The "Coating Suspension11 should be stirred again before use and kept stirring slovty during the coating (spraying) process. 2. Bi-layer Tablet [0177] Examples of the composition of bi-layer tablets for the SGLT-2 inhibitor of this invention (compound (1.9), or a crystalline form (I.9X) of compound (1.9)) + metformin HCI FDC (Film-coated Tablets) is shown in Table 2.
Table 2: Examples of the composition of SGLT-2 inhibitor + Metformin HCI Bi-laver Tablets
[0178] A broad dose range of the SGLT-2 inhibitor 1-chloro-4-(P-D-glucopyranos-1-yl)-2-[4-( (S)-tetrahydrofuran-3-yloxy)-benzylj-benzene, eg. 5 or 12.5 mg, could be used, in which case the amount of binder corn starch or microcrystalline cellulose is adjusted. Instead of corn starch, microcrystalline cellulose could be used. In the further description of the manufacturing procedure only corn starch is described.
Manufacturing procedure (Bi-layer tablets): [0179] The SGLT-2 inhibitor of this invention (compound (I.9), or crystalline form (I.9X) of compound (1.9)) + metformin HCI FDC bi-layer tablets are produced by a high-shear wet granulation process (for SGLT-2 inhibitor-granulate), a fluid-bed granulation process (for metformin HCI-granulate), and bi-layer tableting process with a multi-layer rotary press.
[0180] SGLT-2 inhibitor-granulate: By using a high-shear granulator the active SGLT-2 inhibitor. The overall manufacturing process consisted of following steps: 1. 1) Screen hydroxpropyl cellulose (HPC) 2. 2) Add the intra-granular microcrystalline cellulose portion. SGLT-2 inhibitor, lactose, HPC and croscarmelose sodium to the granulator 3. 3) Granulate the blend with water.
4. 4) Dry the granulate in Fluid bed drier: less than 1.5% LOD 5. 5) Mill the granulation into the blender container o Quadra mill o Quadra mill screen -18 mesh. 6. 6) Screen the following onto milled granulation in the container of a tumble blender o Premix of the colloidal silicon dioxide with a portion of the extra-granular microcrystalline cellulose screened through 20-25 mesh. o Remainder of the extra-granular microcrystalline cellulose and blend. 7. 7) Premix the magnesium stearate with a portion of the blended granulation, screen (18 mesh) onto the remainder of the granulation in the blender.
[0181] Subsequently the "Final Blend A" is produced by final blending in a suitable blender.
[0182] Metformin HCI-qanulate: Metformin HCI and corn starch, fluid-bed granulation is conducted by spraying of "Granulation Liquid" composed of copolyvidon (Kollidon VA64) and purified water. Alternatively, the SGLT-2 inhibitor is added as powder together with metformin-HCI and corn starch to the fluid bed granulator. After finishing of fluid-bed granulation, the granulate is sieved with a suitable screen. The sieved granulate is blended with colloidal anhydrous silica (Aerosil 200) and magnesium stearate as a lubricant.
[0183] Narrative more specific description of the manufacturing process for the Metformin HCI-granulate: 1. a) Metformin HCI is sieved using a screen with a mesh size of 0.5 to1 mm before weighing. 2. b) Copolyvidon is dissolved in purified water at ambient temperature with a propeller mixer to produce the "Granulation Liquid" 3. c) The "Granulation Liquid" is sprayed into the mixture for fluid-bed granulating under dry condition to avoid blocking during granulation. 4. d) At the end of spraying, the resultant granulate is dried at 70 - 80 °C until the desired LOD value (i.e. 0.8 - 2 %, for example 1 - 2 %), in case the LOD is more than 2 %. 5. e) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0 mm. 6. f) The sieved granulate and colloidal anhydrous silica (Aerosil 200) are blended with a suitable blender. Aerosil 200 should be sieved with a 0.5 mm-screen before use. 7. g) Magnesium stearate passed through a 0.5 mm sieve and added into the granulate. Subsequently the "Final Blend B" is produced by final blending in the blender.
[0184] The "Final Blend A" and "Final Blend B" are compressed into bi-layer tablets using a multi-layer rotary press. The tablet cores may be film-coated by an aqueous film-coating suspension, containing hypromellose as film-forming agent, polyethylene glycol or propylene glycol as plasticizer, talc as glidant and the pigments yellow, red, black iron oxide and mixture thereof and titanium dioxide.
[0185] Narrative more specific description of the manufacturing process for the film-coating: 1. a) Hypromellose and polyethylene glycol or propylene glycol are dissolved in purified water with a propeller mixer. Talc, titanium dioxide, and iron oxide (yellow, red or yellow and red) are dispersed in purified water with a homo-mixer. The suspension is added into the hypromellose solution, then mixed with a propeller mixer at ambient temperature to produce the "Coating Suspension". 2. b) The tablet cores are coated with the "Coating Suspension" to the target weight gain to produce the "Film-coated Tablets". The "Coating Suspension" should be stirred again before use and kept stirring slowly during the coating (spraying) process. 3. Tablet-in-Tablet or Bull's eye tablet [0186] Examples of the composition of Tablet-in-Tablet or Bull's eye tablets for the SGLT-2 inhibitor of this invention (compound (1.9), or crystalline form (I.9X) of compound (1.9)) + metformin HCI FDC (Film-coated Tablets) is shown in Table 3.
Table 3: Examples of the composition of compound (1.9), or crystalline form (I.9X) of compound (1.9)) + Metformin HCI FDC Tablet-in-Tablet or Bull's Eve Tablets
[0187] Abroad dose range of the SGLT-2 inhibitor 1-chloro-4-(8-D-glucopyranos-1-yl)-2-[4-( (S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, eg. 5 or 12.5 mg, could be used, in which case the amount of binder corn starch or microcrystalline cellulose is adjusted. Instead of corn starch, microcrystalline cellulose could be used. In the further description of the manufacturing procedure only corn starch is described.
Manufacturing procedure (Tablet-in-Tablet or Bull's eye tablet): [0188] The SGLT-2 inhibitor of this invention (compound (1.9), or crystalline form (I.9X) of compound (1.9)) + metformin HCI FDC Tablet-in-Tablet or Bull's eye tablets are produced by a high-shear wet granulation process (for SGLT-2 inhibitor-granulate), a rotary press (for SGLT-2 inhibitor core-tablet), a fluid-bed granulation process (for metformin HCI-granulate), and press-coating process with a press-coater.
[0189] SGLT-2 inhibitor-granulate : By using a high-shear granulator the active SGLT-2 inhibitor. The overall manufacturing process consisted of following steps: 1. 1) Screen hydroxpropyl cellulose (HPC) 2. 2) Add the intra-granular microcrystalline cellulose portion. SGLT-2 inhibitor, lactose, HPC and croscarmelose sodium to the granulator 3. 3) Granulate the blend with water.
4. 4) Dry the granulate in Fluid bed drier: less than 1.5% LOD 5. 5) Mill the granulation into the blender container o Quadro mill with screen -18 mesh. 6. 6) Screen the following onto milled granulation in the container of a tumble blender o Premix of the colloidal silicon dioxide with a portion of the extra-granular microcrystalline cellulose screened through 20-25 mesh. o Remainder of the extra-granular microcrystalline cellulose and blend. 7. 7) Premix the magnesium stearate with a portion of the blended granulation, screen (18 mesh) onto the remainder of the granulation in the blender.
[0190] Subsequently the "Final Blend" is produced by final blending in the free-fall blender. 8.) The “Final Blend" of the SGLT-2 inhibitor is compressed into tablets with a rotary press.
[0191] Metformin HCI-granulate: Metformin HCI and corn starch, fluid-bed granulation is conducted by spraying of "Granulation Liquid" composed of copolyvidon (Kollidon VA64) and purified water. Alternatively, the SGLT-2 inhibitor is added as powder together with metformin-HCI and corn starch to the fluid bed granulator. After finishing of fluid-bed granulation, the granulate is sieved with a suitable screen. The sieved granulate is blended with colloidal anhydrous silica (Aerosil 200) and magnesium stearate as a lubricant.
[0192] Narrative more specific description of the manufacturing process for the Metformin HCI-granulate: a) Metformin HCI is sieved using a screen with a mesh size of 0.5 to1 mm before weighing. b) Copolyvidon is dissolved in purified water at ambient temperature with a propeller mixer to produce the "Granulation Liquid" d) The "Granulation Liquid" is sprayed into the mixture for fluid-bed granulating under dry condition to avoid blocking during granulation. e) At the end of spraying, the resultant granulate is dried at 70 - 80 °C until the desired LOD value (i.e. 0.8 - 2 %, for example 1 -2 %), in case the LOD is more than 2 %. f) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0 mm. g) The sieved granulate and colloidal anhydrous silica (Aerosil 200) are blended with a suitable blender. Aerosil 200 should be sieved with a 0.5 mm-screen before use. h) Magnesium stearate passed through a 0.5 mm sieve and added into the granulate. Subsequently "Metformin HCI-granulate" (Final Blend) is produced by final blending in the blender.
[0193] The "SGLT-2 inhibitor core-tablets" and "Metformin HCI-granulate” are compressed into Tablet-in-Tablet or Bull's eye tablets using a press-coater. The difference between the Tablet-in-Tablet and Bull's eye tablet is the position of the core tablet.
[0194] Narrative more specific description of the manufacturing process for the Tablet-in-Tablet: 1. a) Fill a half of Metformin HCI-granulate in a die. 2. b) Place a compound (1.9), or crystalline form (I.9X) of compound (1.9)) core-tablet on the surface of Metformin HCI-granulate. 3. c) Cover the core-tablet with second half of Metformin HCI-granulate, then compressed into the tablet (Tablet-in-Tablet).
[0195] Narrative more specific description of the manufacturing process for the Bull's eye tablets: 1. a) Fill Metformin HCI-granulate in a die. 2. b) Place the compound (1.9), or crystalline form (I.9X) of compound (1.9)) core-tablet on the Metformin HCI-granulate in the die, then compressed into the tablet (Bull's eye tablet).
[0196] The tablets may be film-coated by an aqueous film-coating suspension, containing hypromellose as film-forming agent, polyethylene glycol or propylene glycol as plasticizer, talc as glidant and the pigments yellow, red, black iron oxide and mixture thereof and titanium dioxide.
[0197] Narrative more specific description of the manufacturing process for the film-coating: 1. a) Hypromellose and polyethylene glycol or propylene glycol are dissolved in purified water with a propeller mixer. Talc, titanium dioxide, and iron oxide (yellow, red, black or mixture thereof) are dispersed in purified water with a homo-mixer. The suspension is added into the hypromellose solution, then mixed with a propeller mixer at ambient temperature to produce the "Coating Suspension". 2. b) The tablet cores are coated with the "Coating Suspension" to the target weight gain to produce the “Film-coated Tablets". The "Coating Suspension" should be stirred again before use and kept stirring slowly during the coating (spraying) process. 4. SGLT-2 inhibitor-Drug Layering on Metformin HCI Tablet (film-coating for drug-loading) [0198] Examples of the composition of the SGLT-2 inhibitor of this invention (Compound (1.9), or crystalline form (I.9X) of compound (1.9)) + metformin HCI FDC (Film-coated Tablets) which are prepared by drug loading by film-coating on the Metformin HCI Tablet is shown in Table 4.
Table 4: Examples of the composition of Compound (1.9), or crystalline form (I.9X) of compound (1.9)) + Metformin HCI FDC SGLT-2 inhibitor-Coating on Metformin HCI Tablet
[0199] A broad dose range of the SGLT-2 inhibitor 1-chloro-4-(P-D-glucopyranos-1-yl)-2-[4-( ('SJ-tetrahydrofuran-3-yloxy)-benzylj-benzene, eg. 5 or 12.5 mg, could be used, in which case the amount of binder corn starch or microcrystalline cellulose is adjusted. Instead of corn starch, microcrystalline cellulose could be used. In the further description of the manufacturing procedure only corn starch is described.
Manufacturing procedure (SGLT-2 inhibitor-drug layering by film-coating on Metformin HCI Tablet): [0200] The SGLT-2 inhibitor (Compound (1.9), or crystalline form (I.9X) of compound (1.9)) + metformin HCI FDC with drug coating is produced by a fluid-bed granulation process, a conventional tableting process, and film-coating process with three steps: sealcoating, drug-loading and over-coating. The over-coating may be able to be skipped by combining with the drug-loading, if the stability is acceptable.
[0201] Metformin HCI Tablets: Metformin HCI and corn starch, fluid-bed granulation is conducted by spraying of "Granulation Liquid" composed of copolyvidon (Kollidon VA64) and purified water. Alternatively, the SGLT-2 inhibitor is added as powder together with metfomin-HCI and corn starch to the fluid bed granulator. After finishing of fluid-bed granulation, the granulate is sieved with a suitable screen. The sieved granulate is blended wth colloidal anhydrous silica (Aerosil 200) and magnesium stearate as a lubricant. The final blend is compressed into the tablets with a conventional rotary press.
[0202] Narrative more specific description of the manufacturing process for the Metformin HCI-granulate: a) Metformin HCI is sieved using a screen with a mesh size of 0.5 to 1 mm before weighing. b) Copolyvidon is dissolved in purified water at ambient temperature with a propeller mixer to produce the “Granulation Liquid" d) The "Granulation Liquid" is sprayed into the mixture for fluid-bed granulating under dry condition to avoid blocking during granulation. e) At the end of spraying, the resultant granulate is dried at 70 - 80 °C until the desired LOD value (i.e. 0.8 - 2 %, for example 1 -2 %), in case the LOD is more than 2 %. f) The granulate is sieved using a screen with a mesh size of 0.5 to 1.0 mm. g) The sieved granulate and colloidal anhydrous silica (Aerosil 200) are blended with a suitable blender. Aerosil 200 should be sieved with a 0.5 mm-screen before use. h) Magnesium stearate passed through a 0.5 mm sieve and added into the granulate. Subsequently "Final Blend" is produced by final blending in the blender. i) The "Final Blend" is compressed into the tablets with a conventional rotary press.
[0203] Film-coating: The tablets are film-coated by (1) seal-coating: by an aqueous film-coating suspension, containing hypromellose as film-forming agent, polyethylene glycol (Macrogol, especially Macrogol 400, 6000 or 8000) as plasticizer, propylene glycol as alternativ plasticizer, talc as glidant and the pigments yellow iron oxide and/or red iron oxide or mixtures with iron oxide black and titanium dioxide, (2) drug-loading: by an aqueous film-coating suspension, containing hypromellose as filmforming agent, polyethylene glycol or propylene glycol as plasticizer, compound (1.9), or crystalline form (I.9X) of compound (1.9) as drug substance and (3) over-coating: by an aqueous film-coating suspension, containing hypromellose as film-forming agent, polyethylene glycol or propylene glycol as plasticizer, talc as glidant and the pigments yellow iron oxide and/or red and /or black iron oxide and titanium dioxide, [0204] Narrative more specific description of the manufacturing process for the film-coating with a coating machine: 1. a) Hypromellose and polyethylene glycol or propylene glycol are dissolved in purified water with a propeller mixer. Talc, titanium dioxide, and iron oxide (yellow, red, black or yellow and red and black and mixture thereof) are dispersed in purified water with a homo-mixer. The suspension is added into the hypromellose solution, then mixed with a propeller mixer at ambient temperature to produce the "Coating Suspension" for "seal-coating" and "over-coating". 2. b) Hypromellose, polyethylene glycol or propylene glycol are dissolved in purified water with a propeller mixer. Compound (1.9), or crystalline form (I.9X) of compound (1.9) (active drug) is added into the hypromellose solution, then dispersed with a propeller mixer at ambient temperature to produce the "Drug Suspension" for "drug-loading". 3. c) The Metformin HCI tablets are coated with the "Coating Suspension" to the target weight gain to form the "seal-coat". The "Coating Suspension" should be stirred again before use and kept stirring slowly during the coating (spraying) process. 4. d) Following the seal-coating, the "Drug Suspension" is applied to the surface of the Metformin HCI tablets to form the "drug layer" (drug loading). The "Drug Suspension" should be stirred again before use and kept stirring slowly during the coating (spraying) process. The coating end point can be determined by available PAT (Process Analysis Technology). 5. e) After drug loading the "Coating Suspension" is applied to the compound (I.9), or crystalline form (I.9X) of compound (I.9) drug-loaded tablets to form the "over-coat" and to produce the “Film-coated Tablets". The "Coating Suspension" should be stirred again before use and kept stirring slowly during the coating (spraying) process.
Product Description: [0205] The product description of Compound (1.9), or crystalline form (I.9X) of compound (1.9) + Metformin HCI FDC mono-layer tablets (tablet core and film-coated tablets) is shown in Table 8 and Table 9, respectively.
Table 8a: Product Description of Compound (1.9), or crystalline form (I.9X) of compound (1.9) + Metformin HCI FDC Mono-layer Tablets (Tablet Core)
Stability Data: [0206] Stability data of Compound (1.9), or crystalline form (I.9X) of compound (1.9) + Metformin HCI FDC mono-layer tablets (Table 1.1 and 1.7) is shown in the following tables.
Test parameter Initial 60°C glass bottle, with NaCI j 8W j Degradation Metformin (%) <0.2 <0.2 | Total <0.2 1.0 j
Stability Data: [0207] Stability data of Compound (1.9), or crystalline form (I.9X) of compound (1.9) + Metformin HCI FDC mono-layer tablets (Table 1.9 and 1.10) is shown in the following tables. 12.5+500 mg tablets
Test parameter Initial 60°C glass bottle ] 8W | Degradation compound (I.9), or crystalline form (I.9X) of compound (I.9) (%) <0.2 Degradation Metformin (%) <0.2 <0.2 | Total <0.2 | 12.5+500 mg tablets
Test parameter Initial 40°C glass bottle j 8W | Degradation compound (I.9), or crystalline form (I.9X) of compound (I.9) (%) <0.2 | Degradation Metformin (%) <0.2 <0.2 ] Total <0.2 <0.2 J
12.5+500 mg tablets
Test parameter Initial 60°C glass bottle, with NaCI j 8W | Degradation compound (I.9), or crystalline form (I.9X) of compound (1.9)) (%) 13 I Degradation Metformin (%) <0.2 <0.2 | Total <0.2 Ί-3 | 1.25+500 mg tablets
Test parameter Initial 60°C glass bottle | 8W | Degradation compound (I.9), or crystalline form (I.9X) of compound (I.9) (%) <0.2 j Degradation Metformin (%) <0.2 <0.2 j Total <0.2 j 1.25+500 mg tablets
Test parameter Initial 40°C glass bottle ] 8W ] Degradation compound (I.9), or crystalline form (I.9X) of compound (I.9) (%) <0.2 | Degradation Metformin (%) <0.2 <0.2 j Total <0.2 <0.2 [ 36
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
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Claims (13)

1. Fast farmaceutisk sammensætning omfattende SGLT-2-hæmmeren l-chlor-4-(p-D-glukopyranos-l-yl)-2-[4-(('S/)-tetrahydrofuran-3-yloxy)-benzyl]-benzen, metforminhydro-chlorid og en eller flere farmaceutiske excipienser, hvor SGLT-2-hæmmeren er til stede i en doseringsstyrke på 5 mg eller 12,5 mg, og hvor metforminhydrochlorid er til stede i en doseringsstyrke på 500 mg, 850 mg eller 1000 mg, og hvor den faste farmaceutiske sammensætning omfatter copovidon som bindemiddel.A solid pharmaceutical composition comprising the SGLT-2 inhibitor 1-chloro-4- (pD-glucopyranos-1-yl) -2- [4 - (('S /) - tetrahydrofuran-3-yloxy) -benzyl] -benzene , metformin hydrochloride and one or more pharmaceutical excipients wherein the SGLT-2 inhibitor is present at a dosage strength of 5 mg or 12.5 mg and wherein metformin hydrochloride is present at a dosage strength of 500 mg, 850 mg or 1000 mg. and wherein the solid pharmaceutical composition comprises copovidone as a binder. 2. Farmaceutisk sammensætning ifølge krav 1, hvor excipienserne er udvalgt fra gruppen bestående af et eller fyldstoffer indbefattende mikrokrystallinsk cellulose; D-mannitol, majsstivelse og prægelatineret stivelse; et bindemiddel indbefattende copovidon; et smøremiddel indbefattende magnesiumstearat eller natriumstearylfumarat; og et glidemiddel indbefattende kolloid vandfri siliciumdioxid.The pharmaceutical composition of claim 1, wherein the excipients are selected from the group consisting of one or fillers including microcrystalline cellulose; D-mannitol, corn starch and pregelatinized starch; a binder including copovidone; a lubricant including magnesium stearate or sodium stearyl fumarate; and a lubricant including colloidal anhydrous silica. 3. Farmaceutisk sammensætning ifølge krav 2, yderligere omfattende en eller flere blandt følgende: fyldstoffet majsstivelse, smøremidlet magnesiumstearat eller natriumstearylfumarat og glidemidlet kolloid vandfri siliciumdioxid.The pharmaceutical composition of claim 2, further comprising one or more of the following: the filler corn starch, the lubricant magnesium stearate or sodium stearyl fumarate and the lubricant colloid anhydrous silica. 4. Farmaceutisk sammensætning ifølge krav 2, yderligere omfattende en eller flere blandt følgende: fyldstoffet mikrokrystallinsk cellulose, smøremidlet magnesiumstearat eller natriumstearylfumarat og glidemidlet kolloid vandfri siliciumdioxid.The pharmaceutical composition of claim 2, further comprising one or more of the following: the filler microcrystalline cellulose, the lubricant magnesium stearate or sodium stearyl fumarate and the lubricant colloid anhydrous silica. 5. Fast farmaceutisk sammensætning ifølge et eller flere af de foregående krav, omfattende en eller flere af følgende mængder (% efter vægt af samlet overtrukket tabletmasse): 0,1-2,11 % SGLT-2-hæmmer, 47-88 % metformin HCI, 3.9- 8,3 % bindemiddel (f.eks. copovidon), 2.3- 8,0 % fyldstof 1 (f.eks. majsstivelse), 0-4,4 % fyldstof 2 (f.eks. prægelatiniseret stivelse), 0-33 % fyldstof 3 (f.eks. D-mannitol), 0,7-1,5 % smøremiddel (f.eks. magnesiumstearat), 0,05-0,5 % glidemiddel (f.eks. kolloid vandfri siliciumdioxid), 0,00-3,0 % desintegrationsmiddel (f.eks. crospovidon eller croscarmello- senatrium)A solid pharmaceutical composition according to any one of the preceding claims, comprising one or more of the following amounts (% by weight of total coated tablet mass): 0.1-2.11% SGLT-2 inhibitor, 47-88% metformin HCl, 3.9- 8.3% binder (e.g. copovidone), 2.3- 8.0% filler 1 (e.g. corn starch), 0-4.4% filler 2 (e.g. pregelatinized starch), 0-33% filler 3 (eg D-mannitol), 0.7-1.5% lubricant (eg magnesium stearate), 0.05-0.5% lubricant (eg colloidal anhydrous silica ), 0.00-3.0% disintegrant (eg crospovidone or croscarmellose sodium) 6. Fast farmaceutisk sammensætning ifølge et eller flere af de foregående krav, omfattende en eller flere af følgende mængder (% efter vægt af samlet overtrukket tabletmasse): 0,1-2,11 % SGLT-2-hæmmer, 47-88 % metformin HCI, 3.9- 8,3 % copovidon som bindemiddel, 2.3- 8,0 % majsstivelse som fyldstof, 0-4,4 % prægelatiniseret stivelse som fyldstof, 0-33 % D-mannitol som fyldstof, 0,7-1,5 % magnesiumstearat som smøremiddel, 0,05-0,5 % kolloid vandfri siliciumdioxid som glidemiddel, 0,00-3,0 % crospovidon eller croscarmellosenatrium som desintegrations middel.A solid pharmaceutical composition according to any one of the preceding claims, comprising one or more of the following amounts (% by weight of total coated tablet mass): 0.1-2.11% SGLT-2 inhibitor, 47-88% metformin HCl, 3.9- 8.3% copovidone as binder, 2.3- 8.0% corn starch as filler, 0-4.4% pregelatinized starch as filler, 0-33% D-mannitol as filler, 0.7-1.5 % magnesium stearate as lubricant, 0.05-0.5% colloidal anhydrous silica as lubricant, 0.00-3.0% crospovidone or croscarmellose sodium as disintegrant. 7. Farmaceutisk sammensætning ifølge et hvilket som helst af kravene 1 til 6 på tabletdoseringsform.Pharmaceutical composition according to any one of claims 1 to 6 in tablet dosage form. 8. Farmaceutisk doseringsform omfattende en farmaceutisk sammensætning ifølge et eller flere af kravene 1 til 7, kendetegnet ved, at der er tale om en fast farmaceutisk doseringsform, og at doseringsformen er en kapsel eller en tablet.Pharmaceutical dosage form comprising a pharmaceutical composition according to one or more of claims 1 to 7, characterized in that it is a solid pharmaceutical dosage form and that the dosage form is a capsule or tablet. 9. Farmaceutisk doseringsform ifølge et af kravene 1 til 7 til anvendelse i - forebyggelse, hæmning, forsinkelse eller behandling af en stofskifteforstyrrelse udvalgt fra gruppen bestående af type 1-diabetes mellitus, type 2-diabetes mellitus, nedsat glukosetolerance, nedsat fasteblodsukker, hyperglykæmi, postprandial hyperglyk-æmi, overvægt, svær overvægt og metabolisk syndrom; eller - forbedring af glykæmisk styring og/eller reduktion af fasteplasmaglukose, af postprandial plasmaglukose og/eller glykosyleret hæmoglobin HbAlc; eller - forebyggelse, hæmning, forsinkelse eller tilbagerulning af fremadskriden fra nedsat glukosetolerance, insulinresistens og/eller metabolisk syndrom til type 2-diabetes mellitus; eller - forebyggelse, hæmning, forsinkelse eller behandling af en tilstand eller lidelse udvalgt fra gruppen bestående af komplikationer til diabetes mellitus så som grå stær og mikro- og makrovaskulære sygdomme, såsom nefropati, retinopati, neuropati, vævsiskæmi, arteriosklerose, myokardinfarkt, slagtilfælde og perifer arterieokklusi-onssygdom; eller - forebyggelse, hæmning, forsinkelse eller behandling af degeneration af bugspytkir-tel-betaceller og/eller faldende funktionalitet af bugspytkirtel-betaceller og/eller til forbedring og/eller genoprettelse af funktionaliteten af bugspytkirtel-betaceller og/eller genoprettelse af funktionaliteten af bugspytkirtelinsulinsekretion; eller - til forebyggelse, hæmning, forsinkelse eller behandling af sygdomme eller tilstande, der tilskrives en abnorm ophobning af leverfedt; eller - opretholdelse og/eller forbedring af insulinsensitivitet og/eller til behandling eller forebyggelse af hyperinsulinæmi og/eller insulinresistens; hos en patient med behov derfor.Pharmaceutical dosage form according to one of claims 1 to 7 for use in - prevention, inhibition, delay or treatment of a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, glucose tolerance, reduced blood sugar, hyperglycemia, postprandial hyperglycaemia, obesity, severe obesity and metabolic syndrome; or - improving glycemic control and / or reduction of fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbAlc; or - prevention, inhibition, delay or rollback of the progression from impaired glucose tolerance, insulin resistance and / or metabolic syndrome to type 2 diabetes mellitus; or - prevention, inhibition, delay or treatment of a condition or disorder selected from the group consisting of diabetes mellitus complications such as cataracts and micro- and macrovascular diseases such as nephropathy, retinopathy, neuropathy, tissue ischemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterieokklusi-onssygdom; or - preventing, inhibiting, delaying, or treating pancreatic beta cell degeneration and / or decreasing pancreatic beta cell function and / or enhancing and / or restoring pancreatic beta cell function and / or restoring pancreatic pancreatic function; or - for the prevention, inhibition, delay or treatment of diseases or conditions attributed to abnormal accumulation of liver fat; or - maintaining and / or improving insulin sensitivity and / or for the treatment or prevention of hyperinsulinemia and / or insulin resistance; in a patient in need therefore. 10. Farmaceutisk sammensætning til anvendelse ifølge krav 9, hvor patienten er et individ, der er diagnosticeret med en eller flere tilstande udvalgt fra gruppen bestående af overvægt, svær overvægt, indvoldsfedme og bugfedme.The pharmaceutical composition for use according to claim 9, wherein the patient is a subject diagnosed with one or more conditions selected from the group consisting of overweight, severe obesity, intestinal obesity and abdominal obesity. 11. Farmaceutisk sammensætning til anvendelse ifølge krav 9, hvor patienten er et individ, som udviser en, to eller flere af følgende tilstande: (a) et fasteblodsukker eller serumglukosekoncentration på over 110 mg/dl, navnlig over 125 mg/dl; (b) postprandial plasmaglukose lig med eller større end 140 mg/dl; (c) en HbAlc-værdi lig med eller større end 6,5 %, navnlig lig med eller større end 7,0%.The pharmaceutical composition for use according to claim 9, wherein the patient is a subject exhibiting one, two or more of the following conditions: (a) a solid blood sugar or serum glucose concentration greater than 110 mg / dl, in particular greater than 125 mg / dl; (b) postprandial plasma glucose equal to or greater than 140 mg / dl; (c) an HbAlc value equal to or greater than 6.5%, in particular equal to or greater than 7.0%. 12. Farmaceutisk sammensætning til anvendelse ifølge krav 9, hvor patienten er et individ, hvorhos en, to, tre eller flere af de følgende tilstande gør sig gældende: (a) svær overvægt, indvoldsfedme og/eller bugfedme, (b) triglyceridblodindhold >150 mg/dl, (c) HDL-kolesterolblodindhold < 40 mg/dl hos kvindelige patienter og < 50 mg/dl hos mandlige patienter, (d) et systolisk blodtryk >130 mm Hg og et diastolisk blodtryk >85 mm Hg, (e) et fasteblodsukkerindhold >110 mg/dl.The pharmaceutical composition for use according to claim 9, wherein the patient is an individual in which one, two, three or more of the following conditions apply: (a) severe obesity, visceral obesity and / or abdominal obesity, (b) triglyceride blood content> 150 (c) HDL cholesterol blood levels <40 mg / dl in female patients and <50 mg / dl in male patients, (d) a systolic blood pressure> 130 mm Hg and a diastolic blood pressure> 85 mm Hg, (e) a solid blood sugar content> 110 mg / dl. 13. Farmaceutisk sammensætning til anvendelse ifølge krav 9, hvor patienten har utilstrækkelig glykæmisk styring på trods af kost og motion eller på trods af monoterapi med et middel mod sukkersyge, navnlig metformin.The pharmaceutical composition for use according to claim 9, wherein the patient has insufficient glycemic control despite diet and exercise or despite monotherapy with an antidiabetic agent, in particular metformin.
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